View source for 3o0u


==Cathepsin K covalently bound to a cyano-pyrimidine inhibitor with improved selectivity over hERG==
<StructureSection load='3o0u' size='340' side='right'caption='[[3o0u]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3o0u]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O0U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O0U FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O47:3-{2-[(E)-IMINOMETHYL]-6-PROPYLPYRIMIDIN-4-YL}-N,N-DIMETHYL-5-(TRIFLUOROMETHYL)BENZAMIDE'>O47</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3o0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o0u OCA], [https://pdbe.org/3o0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o0u RCSB], [https://www.ebi.ac.uk/pdbsum/3o0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o0u ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[https://omim.org/entry/265800 265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation.
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== Publication Abstract from PubMed ==
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (&gt;1000-fold), displayed a highly attractive overall profile.

Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: Improving selectivity over hERG.,Rankovic Z, Cai J, Kerr J, Fradera X, Robinson J, Mistry A, Finlay W, McGarry G, Andrews F, Caulfield W, Cumming I, Dempster M, Waller J, Arbuckle W, Anderson M, Martin I, Mitchell A, Long C, Baugh M, Westwood P, Kinghorn E, Jones P, Uitdehaag JC, van Zeeland M, Potin D, Saniere L, Fouquet A, Chevallier F, Deronzier H, Dorleans C, Nicolai E Bioorg Med Chem Lett. 2010 Aug 24. PMID:20843687<ref>PMID:20843687</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3o0u" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fradera X]]
[[Category: Uitdehaag JCM]]
[[Category: Van Zeeland M]]